Transcription factors represent a group of molecules within the cell that function to connect the pathway from extracellular signal to intracellular response. Immediately after an environmental stimulus, these proteins which reside predominantly in the cytosol are translocated to the nucleus where they bind to DNA and activate the transcription of their target genes. One such group of transcription factors is the Rel/NF-kappaB family. These transcriptional activators are found in many tissues and are localized in the cytosol as hetero- or homodimers with other members of the family and remain inactive due to the association of the dimer with an inhibitory protein. Rel/NF-kappaB proteins have been shown to be involved in a diverse set of signaling pathways involving the immune response, apoptosis, cancer and growth. cREL is a member of the Rel/NF-kappaB family of transcriptional activators which also includes RelA (p65), RelB, p50 and NF-kappaB (a dimer of p50 and RelA). cREL, the first member of the family to be cloned, was recognized as the cellular homologue of a previously identified oncogene, v-Rel, a product of the avian reticulendotheliosis virus REV-T (Baeuerle and Henkel, Annu. Rev. Immunol., 1994, 12, 141-179).
cREL has been implicated in viral infection. In COS7 and U293 cells, the cREL protein forms a heterodimer with RelA and upregulates the viral enhancer of the HIV-1 virus (Hansen et al., J. Biol. Chem., 1994, 269, 22230-22237).
Manifestations of altered cREL expression have also been demonstrated in studies of transgenic mice lacking either the entire cREL gene or the COOH terminus of the protein, which is responsible for transcriptional activation. In these studies, expression of a truncated form of the cREL protein resulted in a more severe phenotype than the complete absence of the protein. Mice expressing the shorter protein showed defects in immune functions in addition to enlarged spleens, bone marrow hyperplasia, and lymphoid hyperplasia in the liver, lungs, and stomach (Carrasco et al., J. Exp. Med., 1998, 187, 973-984).
Members of the Rel/NF-kappaB family are strong transcriptional activators of the genes for inflammatory cytokines, acute phase response proteins and cell adhesion molecules. These molecules have been implicated in disorders such as toxic shock, tissue damage resulting from ischemia reperfusion and graft-vs-host reactions (Ghosh et al., Annu. Rev. Immunol., 1998, 16, 225-260). Taken together, these findings suggest that the members of the Rel/NF-kappaB family would make good targets in an effort to downregulate the inflammatory response.
There is also some evidence that cREL plays a role in the development of cancer. It has been shown that the expression of the cREL gene is upregulated during the stimulation of B and T cells and that the human cREL gene is rearranged in some large T-cell lymphomas (Baeuerle and Henkel, Annu. Rev. Immunol., 1994, 12, 141-179).
To date, strategies aimed at inhibiting cREL function have involved the use of the gene knockout approach (Carrasco et al., J. Exp. Med., 1998, 187, 973-984) and antisense vector technology (Himes et al., Immunity, 1996, 5, 479-489). Experiments including gene knockout of the relA and cREL genes in mice have shown that Rel/NF-kappaB transcription factors are essential for transcriptional activation of cytokine genes (Carrasco et al., J. Exp. Med., 1998, 187, 973-984). Himes et al. have used a plasmid expressing the unique region of the cREL coding sequence, inserted in the antisense orientation, cotransfected into Jurkat cells along with GM-CSF and IL-2 promoter reporter transcripts, to demonstrate that cREL is important for the function of these promoters.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of cREL and there remains a long felt need for additional agents capable of inhibiting cREL function.